CLDN18.2, a member of the Claudin family of tight junction proteins, is a transmembrane structural protein critical for maintaining epithelial barrier integrity. Under normal physiological conditions, CLDN18.2 exhibits highly restricted expression in the differentiated epithelial cells of gastric mucosa, where its epitopes remain largely inaccessible due to intercellular tight junctions. However, malignant transformation disrupts cellular polarity and tight junction architecture, leading to CLDN18.2 overexpression and surface exposure in 16-86% of gastric adenocarcinomas, 60% of pancreatic tumors, and subsets of esophageal, ovarian, and lung cancers. This tumor-selective expression pattern, combined with preserved membrane localization in neoplastic cells, makes CLDN18.2 a compelling therapeutic target.
4-1BB (also known as CD137 or TNFRSF9) is a type I transmembrane glycoprotein belonging to the tumor necrosis factor receptor superfamily (TNFRSF). It consists of 255 amino acids with a molecular weight of ~28 kDa, featuring an extracellular domain containing four cysteine-rich motifs, a transmembrane helix, and an intracellular domain critical for downstream signaling. Primarily expressed on activated T cells and natural killer (NK) cells, 4-1BB is upregulated upon T-cell receptor engagement and interacts with its ligand 4-1BBL, which is predominantly displayed on antigen-presenting cells (APCs) like dendritic cells and macrophages. This receptor-ligand interaction recruits TRAF adaptor proteins (TRAF1, TRAF2, TRAF3) to form signalosomes, activating NF-κB and MAPK pathways that enhance T-cell proliferation, cytotoxic activity, and pro-inflammatory cytokine production, while suppressing apoptosis through upregulated anti-apoptotic proteins like Bcl-2. As a pivotal co-stimulatory molecule in adaptive immunity, 4-1BB has emerged as a promising target for cancer immunotherapy.